Interleukin-6 (IL-6)
Interleukin-6 (“IL-6”) is a multifunctional cytokine involved in numerous biological processes such as the regulation of the acute inflammatory response, the modulation of specific immune responses including B- and T-cell differentiation, bone metabolism, thrombopoiesis, epidermal proliferation, menses, neuronal cell differentiation, neuroprotection, aging, cancer, and the inflammatory reaction occurring in Alzheimer's disease. See Papassotiropoulos, et al. (2001) Neurobiology of Aging 22: 863-871.
IL-6 is a member of a family of cytokines that promote cellular responses through a receptor complex consisting of at least one subunit of the signal-transducing glycoprotein gp130 and the IL-6 receptor (“IL-6R”) (also known as gp80). The IL-6R may also be present in a soluble form (“sIL-6R”). IL-6 binds to IL-6R, which then dimerizes the signal-transducing receptor gp130. See Jones (2005) Immunology 175: 3463-3468.
IL-6 is a pleiotropic pro-inflammatory cytokine, which regulates the acute phase response and the transition from the innate to the adaptive immune response. IL-6 increases hepatic synthesis of proteins that are involved in the ‘acute phase response’ leading to symptoms such as fever, chills, and fatigue. It stimulates B cell differentiation and secretion of antibodies and prevents apoptosis of activated B cells. IL-6 activates and induces proliferation of T cells and in the presence of IL-2, induces differentiation of mature and immature CD8 T cells into cytotoxic T cells. IL-6 is also involved in the differentiation of Th17 cells and IL-17 production and inhibits regulatory T cells (Treg) differentiation. IL-6 also activates osteoclasts, synoviocytes, neutrophils, and other hematopoietic cells. Park, et al. (2007) Bulletin of the NYU Hospital for Joint Diseases 65 (suppl 1): S4-10; Guerne, et al. (1989) J Clin Invest. 83(2): 585-92; Houssiau, et al. (1988) Arthritis Rheum. 31(6): 784-8; Nishimotor, et al. (2006) Nat Clin Pract Rheumatol. 2(11): 619-26; Kishimoto (1989) Blood 74(1): 1-10; and Van Snick (1990) Annu Rev Immunol. 8: 253-78.
In humans, the gene encoding IL-6 is organized in five exons and four introns, and maps to the short arm of chromosome 7 at 7p21. Translation of IL-6 RNA and post-translational processing result in the formation of a 21 to 28 kDa protein with 184 amino acids in its mature form. See Papassotiropoulos, et al. (2001) Neurobiology of Aging 22:863-871.
The function of IL-6 is not restricted to the immune response as it acts in hematopoiesis, thrombopoiesis, osteoclast formation, elicitation of hepatic acute phase response resulting in the elevation of C-reactive protein (CRP) and serum amyloid A (SAA) protein. It is known to be a growth factor for epidermal keratinocytes, renal mesangial cells, myeloma and plasmacytoma cells. Grossman, et al. (1989) Prot Natl Acad Sci. 86(16): 6367-6371; Horii, et al. (1989) J Immunol. 143(12): 3949-3955; and Kawano, et al. (1988) Nature 332: 83-85. IL-6 is produced by a wide range of cell types including monocytes/macrophages, fibroblasts, epidermal keratinocytes, vascular endothelial cells, renal messangial cells, glial cells, condrocytes, T and B-cells and some tumor cells. Akira, et al. (1990) FASEB J. 4(11): 2860-2867. Except for tumor cells that constitutively produce IL-6, normal cells do not express IL-6 unless appropriately stimulated.
Elevated IL-6 levels have been observed in many types of cancer, including breast cancer, leukemia, ovarian cancer, prostate cancer, pancreatic cancer, lymphoma, lung cancer, renal cell carcinoma, colorectal cancer, and multiple myeloma. See, e.g., Chopra, et al. (2004) MJAFI 60:45-49; Songur, et al. (2004) Tumori 90:196-200; Blay, et al. (1992) Cancer Research 52: 3317-3322; Nikiteas, et al. (2005) World J. Gasterenterol. 11:1639-1643; reviewed in Heikkila, et al. (2008) Eur J Cancer 44:937-945. Clinical studies (reviewed in Trikha, et al. (2003) Clinical Cancer Research 9: 4653-4665) have shown some improvement in patient outcomes due to administration of various anti-IL-6 antibodies, particularly in those cancers in which IL-6 plays a direct role promoting cancer cell proliferation or survival.
As noted above, IL-6 stimulates the hepatic acute phase response, resulting in increased production of CRP and elevated serum CRP levels. For this reason, C-reactive protein (CRP) has been reported to comprise a surrogate marker of IL-6 activity. Thus, elevated IL-6 activity can be detected through measurement of serum CRP. Conversely, effective suppression of IL-6 activity, e.g., through administration of a neutralizing anti-IL-6 antibody, can be detected by the resulting decrease in serum CRP levels.
IL-6 is believed to play a role in the development of a multitude of diseases and disorders, including but not limited to fatigue, cachexia, autoimmune diseases, diseases of the skeletal system, cancer, heart disease, obesity, diabetes, asthma, Alzheimer's disease and multiple sclerosis. See, e.g., WO 2011/066374, WO 2011/066371, WO 2011/066378, and WO 2011/066369.
A recent clinical trial demonstrated that administration of rosuvastatin to apparently healthy individuals having elevated CRP (greater than 2.0 mg/l) reduced their CRP levels by 37% and greatly decreased the incidence of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes. Ridker et al., N Engl J Med. 2008 Nov. 9 [Epub ahead of print].
In addition to its direct role in pathogenesis of some cancers and other diseases, chronically elevated IL-6 levels appear to adversely affect patient well-being and quality of life. For example, elevated IL-6 levels have been reported to be associated with cachexia and fever, and reduced serum albumin. Gauldie, et al. (1987) PNAS 84: 7251-7253; Heinric, et al. (1990) Biochem J. 265(3): 621-636; Zamir, et al. (1993) Metabolism 42: 204-208; Zamir, et al. (1992) Arch Surg 127: 170-174. Inhibition of IL-6 by a neutralizing antibody has been reported to ameliorate fever and cachexia in cancer patients, though improvement in these patients' serum albumin level has not been reported. Emille, et al. (1994) Blood 84: 2472-2479; Blay, et al. (1992) Cancer Research 52: 3317-3322; Bataille, et al. (1995) Blood 86: 685-691.
Anemia
Anemia is a condition where a decrease in the number of red blood cells (RBCs) or hemoglobin results in a diminished ability of the blood to carry oxygen. A cardinal sign of anemia is a serum hemoglobin level less than about 14.0 g/dL for men and less than 12.0 g/dL for women (or less than about 11.0 g/L hemaglobin for both men and women). See Auerbach, et al. (2004) Journal of Clinical Oncology 22(7): 1301-1307. Symptoms of anemia generally include fatigue, lack of energy, lightheadedness or dizziness, especially when sitting up rapidly, or standing, shortness of breath, headaches, a pale appearance, rapid heart rate or palpitations, and chest pain. Anemia may be experienced in patients with cancer (e.g., cancer-related anemia), as well as patients undergoing chemotherapy (e.g., chemotherapy-related anemia), radiotherapy (e.g., intensity-modulated radiotherapy (IMRT)), or drug therapy (e.g., drug-induced immune hemolytic anemia (DIIHA)). Garratty (2009) Hematology 1: 73-79; Hinkel, et al. (2010) Journal of the National Comprehensive Cancer Network 8(7): S-38-S-55;
Anemia is common in cancer where about 30% of newly-diagnosed untreated cancer patients exhibit anemia and 75% of cancer patients suffering from anemia at some time during the illness. Over 62% of cancer patients experience anemia during treatment and 38% suffer from anemia during follow-up. Cancer-related anemia has been linked to IL-6 expression in mouse models inoculated with IL-6 producing tumor cells. This cancer-related anemia was successfully prevented by blocking the IL-6 receptor by administration of an anti-IL-6 receptor antibody. Mori, et al. (2009) Biomedical Research 30(1): 47-51; Groopman & Itri (1999) Journal of National Cancer Institute 91(19): 1616-1634; and Prabhash, et al. (2011) Indian J Cancer 48: 1-10.
Anemia a major side effects of chemotherapy. Common symptoms of anemia include fatigue, lack of energy, dizziness, headaches, diminished sex drive, rapid heartbeat, inability to concentrate, paleness, and shortness of breath. Seventy-eight percent of chemotherapy patients experience fatigue. “Chemotherapy-Related Anemia Guide.” Patient Advocate Foundation Website (2011). In response to chemotherapy the patient experiences an inflammatory response including the production of IL-6 which acts on the liver to produce hepcidin which, in turn, inhibits ferroportin, macrophage iron release, and intestinal iron absorption. Thus, IL-6 production, via hepcidin, causes to a drop in iron level and leads to anemia. Inflammatory cytokines also appear to affect other important elements of iron metabolism, including decreasing ferroportin expression, and probably directly blunting erythropoiesis by decreasing the ability of the bone marrow to respond to erythropoietin. Nemeth, et al. (2004) J Clinical Invest. 113(9): 1251-3 and Andrews (2004) The Journal of Clinical Investigation 113(9: 1251-1253; See also Atkins, et al. (1995) Blood 86(4): 1288-1291.
Treatment of anemia includes blood transfusion, iron supplements (e.g., oral or intravenous), and medications that stimulate the formation of red blood cells (e.g., Epoetin alfa (Epogen®, Procrit®) and Darbepoetin alfa (Aranesp®). See Groopman & Itri (1999) Journal of the National Cancer Institute 91(19): 1616-1634. However, many patients with anemia, including chemotherapy-associated anemia do not response well to blood transfusion, iron supplements, or erthyropoietin therapy. See, e.g., Auerbach, et al. (2004) Journal of Clinical Oncology 22(7): 1301-1307 and Smith, et al. (2008) Journal of Clinical Oncology 26(7): 1040-1050. Therefore, a need exists for an improved therapeutics for anemia including chemotherapy-associated anemia. The invention described herein provides compositions IL-6 antagonists, including anti-IL-6 antibodies and antibody fragments thereof, and methods of use which may be used for the prevention and treatment of anemia, including anemia associated with chemotherapy, anemia associated with radiotherapy, and drug-induced immune hemolytic anemia (DIIHA).